Treatment of liver and spleen illnesses by herbs: Recommendations of Avicenna's heritage "Canon of Medicine".

Objective
Avicenna (Abu Ali al-Hossein ibn Abdullah ibn Sina) who had a special attention toward diseases treatments, gathered results of ages of herbal medicine experiments on humans and animals in his book "Al-Qānūn fī Ṭibb" or "The Canon of Medicine", which is a reliable book in Iranian traditional medicine. The aim of this research was to build a reliable list of plants effective against liver and spleen diseases, based on Avicenna's book (volume 2).


Materials and Methods
By studying the monographs, introduced agents that have been effective in liver and spleen diseases were identified. Upon their origin and effectiveness in diseases of the liver, spleen or both, treatments were organized.


Results
From a huge number of drugs, 163 plants from 73 families were found to be effective in treatment of liver and spleen illnesses. In addition, 30 non-herbal agents effective in treatment of liver diseases were detected. The Lamiaceae family have the most effective herbs for treatment of diseases of the liver, spleen or both. Hemp Agrimony, Irsā, and Fūdhanj achieved the highest scores.


Conclusion
The effects of different plants on liver and spleen diseases were indicated in Avicenna's book. Due to the report on the above book, further studies needed specially on the effect of Irsā (Iris ensata) and family Lamiaceae on liver and spleen diseases.


Introduction
The largest organ in the body is the liver, comprising about 2 percent of the total body weight; in an adult with average body mass, the liver is about 1.5 kg. The liver performs many different functions including: 1) filtration and storage of blood; 2) metabolism of carbohydrates, proteins, fats, hormones, and foreign chemicals; 3) formation of bile; 4) storage of vitamins and iron; and 5) formation of coagulant factors (Hall, 2015). Liver diseases are conditions that affect the liver. The liver is prone to diseases due to multidimensional functions and its location (Kumar et al., 2014). The efficiency of current synthetic agents in treating chronic liver disease is not satisfactory and these chemicals have undesirable side effects. Thereby, numerous phytochemicals and medicinal herbs, as alternative and complementary treatments, have been investigated for chronic liver diseases (Hong et al., 2015). Iranian traditional medicine (ITM) has been used for prevention, diagnosis, and treatment of diseases and this medicine works based on the humor theory of temperament in which, the liver is one of the most important organs in the body (Akbarzadeh et al., 2015).
Al-Hossein Abu-Ali Ben Abdullah, Ibn Sina, (known as Sheikh al-Rais (or the Prince of the physicians) and in the West as Avicenna, 980-1037 AD) was an extremely talented individual. Avicenna practiced philosophy, astronomy, geometry, mathematics, and medicine as well as poetry and music. Although medicine was not his main area of interest, he became famous as a physician due to the desperate need for thoughtful medical personnel in the Persian kingdom. Among Avicenna's works, his medical book Al-Qānūn fī Ṭibb, known as Canon in the Western Hemisphere, has a great scientific and historical value. Canon is written in three parts. Part I covers the anatomy and physiology of the human body; Part II includes the description, signs, and symptoms of the disease and Part III describes the treatment of disease and prophylactic measures to prevent disease. For treatment of most diseases, he used food, psychotherapy , and medicinal plants (Qayumi, 1998). Arturo Castiglioni appreciated Avicenna's Canon: "The clarity of the clinical histories, the accuracy of the therapeutic indications, constructed logically and without dangerous exaggerations, and the eloquence of his forcible style were sufficient to confer on this book up to the end of the seventeenth century an almost indisputable authority in the minds of the physicians of all countries" (Galdston, 1955).
Acute liver disease damages the spleen in long term. In Book 2 (the Materia Medica) of Canon, Avicenna alphabetically listed about 806 simple medical agents (of floral, mineral, and animal origin) that were used at the time. Each agent may have different possible general actions, followed by specific properties listed according to symptoms of liver and spleen diseases. In floral monographs of Canon, we found that Avicenna has found that some herbs cure some symptoms so we considered such symptoms and searched for herbs with such properties.

Materials and Methods
In our evaluation, we used different versions of the Canon book available at: (https://sites.google.com/site/avicennacano n1a/canon-web-htm). This library was created by Dr. Hossein Hatami and is also accessible through the Bu Ali Sina Scientific and Cultural Foundation website (http://www.buali.ir/).
The following versions of the Canon were used in our study: 1) The corrected version of Canon in Persian (Sina, 2010), 2) Arabic manuscript of the Canon (Ibn Sina, 2005), and 3) Translated version of the Canon in English (Sīnā, 1998). As the first step, to indicate which herbs have hepatoprotective and other effects for liver diseases, the 2nd volume of Canon was searched. These items were mutually compared and evaluated. Subsequently, data were collected based on different plant species in the areas of healing, and protection. The flow chart of the study is presented in Figure 1.

Statistical analysis
The average values for results are expressed as a mean± standard error of mean (SEM). Statistical analysis was performed using the Statistical Package for the Social Science (IBM SPSS statistics version 23) program for Windows. Statistical significance of differences between groups was evaluated using nonparametric statistics, the relationship between the numbers of herbs in each family to score of herbs was shown by the Kruskal-Wallis test p<0.05 was considered statistically significant. Graphs were created with Excel 2013 software (Microsoft office 2013).

Results
Avicenna introduced 193 agents as they were effective on the liver and spleen. Their characteristics are presented in four categories according to the origin of agent in Tables 1-6 which present basic information such as common name, Persian name, Arabic name, scientific name, family, used parts (i.e. root, fruit, etc.)/ mode of consumption (fried, roasted, etc.) or preparation (enema, smell, etc.), diseases for which the agent was prescribed and finally score.

Plants
We reviewed all herbs mentioned in the 2 nd volume of Canon and found a total of 163 plants used for liver and spleen illnesses. These plants belong to 73 different families. These herbs included medicinal, poisonous, ornamental and economic plants and weeds that are presented in Tables 1-3. According to their effectiveness, they are categorized as effective on liver Table 1, spleen Table 2 and both liver and spleen Table 3. The second volume of the canon book consists of a series of monographs each one describing different properties of one medicinal herb. The monograph name that described the properties of No. 92 herb is lost during repeated transcription through ages so it has indicated as "???" in Table 1. Herb number 93 is a type of endive with no scientific name.  The most common effective plants prescribed for liver or spleen diseases or both, are shown in Figure 2. Figure 3 shows the plant families (i.e. Lamiaceae, Fabaceae, Apiaceae, Rosaceae, Asteraceae, Solanaceae, and Brassicaceae) with the largest contribution to development of treatments against liver and spleen diseases.

Animals
The majority of the 17 agents of animal's origin including animal, organs or animal physiological fluids used as medication. In certain cases, especially for insects, the whole body was used, and in other cases, the animal's urine or even the milk was used. The animals and their applications are presented in Table 4.
The used animals can be divided into groups according to their availability, such as domesticated animals, such as jennet, goat, camel, cow, and others such as locust and worms. Wild animals, for example, wolf, sand grouse, red-headed partridge, hedgehog, porcupine, antelope, and stag. Various organs, and products of exotic animals, species such as Spanish fly, coral, oyster have been used in order to cure liver and spleen diseases

Minerals
We were able to identify 8 materials of mineral origin (Table 5). The use of such agents in medicine has been well-known throughout history.

Agents of other origins
Five medicinal agents that were processed from animal or plant materials or agents of mixed or unknown origin are presented in Table 6.

Discussion
The overwhelming majority (84.45%) of agents that served as simple drugs were derived only from plants (see Table 7). The proportion of materials derived from animals and animal organs is small (8.80%), and minerals represent an even smaller proportion (4.14%).
Based on our survey of Canon, 163 herbal parts which exert therapeutic effects on the liver and spleen, were found. In this book, some items refer to one herb Ṭarfūlis and Ṭūqriūs both refer to Teukrion or some items are parts of one herb and have different names e.g. Ḥiltit is gum and Maḥrūth is the root of Anjudhān so the last two have same scientific name of Asafoetida in the Tables.
In old manuscripts, there are different descriptions for identical herb so different scientific names have been proposed for the same herb. Prof. Ghahraman and Prof. Okhovvat have introduced appropriate scientific names for old names; in the present study, we used scientific names according to their suggestions (Ghahreman and Okhovvat, 2004).
From antiquity until now herbalist and medicinal experts had a quest to find the most effective herb that has the richest source of medicinal material, in order to use it in liver tonics and other formulas. Our research revealed that the effective herbs are not limited to one family but the most frequently used herbs belong to several families that are given in Figure 3. Some families like Laminacea have higher numbers of herbs that are frequently used as effective therapeutics for spleen and liver diseases. We propose to study the herbs of this family and other families noted in Figure 2 in order to find the most effective herb for treatment of liver and spleen diseases.
According to the number of effects that every herb has, as prescribed by Avicenna as effective on liver or spleen diseases or both, the herbs were scored (Figure 2). Ghāfith (Eupatorium cannabinum) was named "The eupatorion of Avicenna" (Tobyn et al., 2016) in old times, is one of the highly scored herbs. The present studies demonstrated choleretic and hepatoprotective effects of hemp agrimony (Lexa et al., 1989) although it contains pyrrolizidine alkaloids (Edgar et al., 1992;Hendriks et al., 1987) which have hepatotoxic and potentially carcinogenic and genotoxic effects and essential oils of E. cannabinum is notably toxic (Judzentiene et al., 2016). On the other hand, the effects of a plant such as Irsā (Iris ensata) which has the highest score ( Figure  1), on the liver or spleen, have not yet been reported and its medicinal use had been uncertain or unknown according to lack of articles is considered a good candidate for future investigations. Fūdhanj (Mentha piperita) which also gained a high score was used successfully by Avicenna as a drug, for treatment of liver and spleen diseases. It was shown that M. piperita causes lipid peroxidation and hepatic damage in a dose-dependent manner (Akdogan et al., 2004). It has hepatotoxic potential (Douros et al., 2016) and moderately severe adverse effects (Posadzki et al., 2013), further studies in this field are needed. Meanwhile, M. piperita has radioprotective properties against gamma irradiation which is probably mediated via its antioxidant and free radical scavenging activities of leaf extract (Samarth et al., 2006); also, this plant may be useful for reducing the side effects of arsenic-induced hepatopathy (Sharma et al., 2007). Afsantin (Artimisia absinthium) is another high-score herb which exhibits hepatoprotective action partly through microsomal drug metabolizing enzymes (MDME) inhibitory action (Gilani and Janbaz, 1995), has significant antioxidant activity and protects the liver and kidney (Kharoubi et al., 2008) probably through its immunomodulatory activity (Amat et al., 2010). Also, this plant was considered for reducing hepatic damage and it may serve as an alternative medicine in hepatic conditions (Saxena and Shukla, 2012).
These results show a need for a close scrutiny in methods of planting, harvesting, processing, extraction and preparing a single or combination formula that affects remedies and practice of ancient medicine. In order to prepare a suitable herbal drug for the treatment of complicated diseases such as liver cirrhosis and hepatocellular carcinoma, according to Avicenna book, further studies are needed to make an effective drug for liver or spleen diseases is promising.
Through analysis of 806 therapeutic items of Avicenna 2 nd volume of Canon, we prepared a list of agents that are effective in three main areas namely, liver, spleen, and liver & spleen diseases. The current study indicates the necessity of deep analysis, study and further assessment of listed items.

Acknowledgment
We appreciate Dr. Hossein Hatami for his efforts in establishing such useful database of Avicenna and other Iranian traditional medicine (ITM) scientist's books in Bu-Ali Sina scientific & cultural foundation site.